This grant represents the first renewal of the UM EDRN Biomarker Development Lab (BDL) which was initiated 5 years ago. During this brief time period, our group has characterized a number of important prostate cancer biomarkers, the most noteworthy being the TMPRSS2-ETS gene fusions found in a majority of prostate cancers. This discovery led to first inaugural AACR Team Science Award in 2007. Looking forward, we propose extending our work in the discovery and refinement of biomarkers to facilitate the accurate diagnosis of prostate cancer using the TMPRSS2-ETS rearrangements as a foundation. We will also take on the significant mission of developing biomarkers to predict aggressive prostate cancer with the goal of distinguishing indolent from aggressive prostate cancer either prior to diagnosis or at the time of biopsy diagnosis. This study takes a systems biology approach to develop clinically relevant prostate cancer biomarkers for detection and risk assessment. In Aim 1, we will extend work from the prior funding period to develop prostate cancer specific biomarkers to accurately diagnose prostate cancer and thus decrease unnecessary biopsies. Aims 2 and 3 focus on the important clinical need to develop biomarkers to distinguish significant from insignificant disease. Aim 2 will use high grade cancer as a surrogate of aggressive disease and Aim 3 we will use two clinically developed risk assessment tools as a surrogate measure of aggressive disease. A biomarker for aggressive disease would impact screening detection and clinical management of prostate cancer. The primary platform technologies we will employ (and have credible expertise) include next generation transcriptome sequencing, Affymetrix SNP arrays, lllumina DASL, Luminex xMAP-based multiplex antigen panels and mass spectrometry based metabolomics. The development of prostate cancer biomarkers for accurate diagnosis and risk assessment are urgently needed as recognized by the EDRN. Our proposal is highly ambitious given the wide range of discovery platforms proposed. Our team approach also extends beyond our BDL and into the EDRN Clinical Validation Center (CVC) where both PIs of this application have played roles in the Michigan/Harvard/WCMC CVC collection of over 1800 samples on EDRN protocol. Finally, our group has actively participated in the EDRN biomarker community and anticipates continuing to work with other BDL and CVCs to facilitate the overall mission of the EDRN.